MONOCLONAL ANTIBODY-BASED STRATEGIES FOR TREATMENT OF BREAST CANCER

我们的目标是开发有效的放射免疫疗法，使用人源化 转移性和/或复发性乳腺癌的单抗。 我们建议评估和克服两个障碍：能力有限 仅通过这种方法就可以提供杀瘤辐射剂量 免疫结合物的免疫原性。我们利用了一种新的， 针对400kD乳腺的人源化BRE-3单抗 上皮粘蛋白抗原，并用111In(111In)MX标记它- DTPA金属络合剂。在12/15年中，我们发现了72个已知病变中的86% 病人。所有U肿瘤患者均表达BRE-3抗原， 通过对先前获得的组织进行免疫组织化学染色进行评估。 高效液相色谱法测定血清中放射性标记抗体的生物半衰期 所有患者的平均时间为56125.4小时。毒性很小，而且 可预测的；然而，检测到人抗鼠免疫球蛋白抗体后 治疗7/15例。我们假设人性化的BRE-3 与90Y(90Y)络合的单抗将是一种有效的 转移性乳腺癌的治疗及其联合治疗 使用拓扑替康治疗将提高疗效。持续输注 纽约大学广泛探索的一种拓扑异构酶I抑制剂显示 在毒性最小的I期试验中乳腺癌的活性。在……里面 小鼠模型，这两个代理的新组合提供了 与单独使用每种药物相比，疗效显著。我们的特定 目的如下：1)开发有效的放射免疫疗法 分次剂量方案联合90Y MX-DTPA治疗乳腺癌 人源化抗BRE-3；2)确定最大耐受量(MTD) 联合剂量分级90Y MX-DTPA人源化BRE-3抗体的研制 I期剂量递增试验中持续输注拓扑替康； 3)评价90Y MX-DTPA联合治疗的潜在疗效 人源化BRE-3和拓扑替康在MTD的II期临床试验 转移性或复发性乳腺癌患者。

Our goal is to develop effective radioimmunotherapy using humanized monoclonal antibodies for metastatic and/or recurrent breast cancer. We propose to evaluate and overcome two obstacles: the limited ability to deliver tumoricidal radiation doses by this method alone and the immunogenicity of the immunoconjugates. We have utilized a new, humanized BrE-3 monoclonal antibody directed against a 400-kD breast epithelial mucin antigen and labeled it with a 111Indium (111In) MX- DTPA metal chelator. We detected 86% of 72 known lesions in 12/15 patients. All the patientsU tumors expressed the BrE-3 antigen, as assessed by immunohistochemical staining of previously obtained tissue. Biological half-life of radiolabeled antibody in serum measured by HPLC averaged 56125.4 hours across all patients. Toxicity was mild and predictable; however, human anti-mouse IgG antibody was detected after treatment in 7/15 patients. We hypothesize that humanized BrE-3 monoclonal antibody complexed with 90Yttrium (90Y) will be an effective therapy against metastatic breast carcinoma and that combining this therapy with topotecan will enhance efficacy. Continuous infusion of a topoisomerase I inhibitor, explored extensively at NYU, has shown activity in breast cancer in phase-I trials with minimal toxicity. In the mouse model, the novel combination of these two agents provides significant therapeutic efficacy over each agent alone. Our specific aims are as follows: 1) to develop effective radioimmunotherapy of breast cancer using a fractionated dose regimen and 90Y MX-DTPA humanized anti-BrE-3; 2) to determine the maximum tolerated dose (MTD) using combined dose-fractionated 90Y MX-DTPA humanized BrE-3 antibody and continuous infusion topotecan in a phase-I dose-escalation trial; and 3) to assess the potential efficacy of combined 90Y MX-DTPA humanized BrE-3 and topotecan at MTD in a phase-II clinical trial in patients with metastatic or recurrent breast cancer.